Journal
CELL DEATH & DISEASE
Volume 9, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-017-0255-5
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Funding
- National Natural Science Foundation of China [81173379]
- Torch Plan Project [XH20150108]
- Open Tending Project for the Construction of High-Level University [A1-AFD018161Z1515]
- research and innovation teams of Guangzhou University of Chinese Medicine [2016KYTD06]
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Betulin (BT), a pentacyclic lupine-type triterpenoid natural product, possesses antitumor activity in various types of cancers. However, its clinical development was discouraged due to its low biological activities and poor solubility. We prepared lup-20(29)-en-3 beta,28-di-yl-nitrooxy acetate (NBT), a derivative of BT, that was chemically modified at position 3 of ring A and C-28 by introducing a NO-releasing moiety. This study mainly explored the mechanism of NBT in treating breast cancer through the crosstalk between apoptosis and autophagy in mitochondria. NBT possessed a potent antiproliferative activity in MCF-7 cells both in vitro and in vivo. Mechanically, NBT affected cell death through the mitochondrial apoptosis pathway and autophagy. NBT induced cell cycle arrest in the G(0)/G(1) phase by decreasing the expression of cyclin D1. It also induced mitochondrial apoptosis by increasing the expression of Bax, caspase-9, and poly(ADP-ribose) polymerase and mitochondrial membrane potential loss and leaks of cytochrome c (Cyt C) from mitochondria in MCF-7 cells and decreasing the expression of mitochondrial Bcl-2. We further demonstrated whether chloroquine (CQ), which inhibits the degradation of autophagosome induced by NBT, affects the proliferation of MCF-7 cells compared with NBT. The experiments inferred that the combination of NBT and CQ significantly promoted MCF-7 cell mitochondria to divide and Cyt C to be released from mitochondria to the cytoplasm, resulting in an increased apoptosis rate. The in vivo experiments showed that NBT inhibited the growth of MCF-7 tumor via the apoptosis pathway, and its effect was similar to 5-fluorouracil.
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